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Last update 08 May 2025

EFHD2

Last update 08 May 2025

Basic Info

Synonyms

EF-hand domain family member D2, EF-hand domain-containing protein D2, EFHD2

+ [3]

Introduction

May regulate B-cell receptor (BCR)-induced immature and primary B-cell apoptosis. Plays a role as negative regulator of the canonical NF-kappa-B-activating branch. Controls spontaneous apoptosis through the regulation of BCL2L1 abundance.

Drugs associated with EFHD2

CN117186188

Patent Mining

Target

EFHD2

Mechanism-

Active Org.

The Naval Medical University of PLA

Originator Org.

The Naval Medical University of PLA

Active Indication

Metabolic dysfunction-associated steatotic liver disease

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with EFHD2

100 Translational Medicine associated with EFHD2

0 Patents (Medical) associated with EFHD2

Literatures (Medical) associated with EFHD2

01 Dec 2024·Phytomedicine

Swiprosin-1 participates in the berberine-regulated AMPK/MLCK pathway to attenuate colitis-induced tight junction damage

Article

Author: Zhang, Wenzhao ; Dong, Xiaohui ; Lu, Xin ; Zhong, Yuting ; Li, Ling ; Wang, Zhibin ; Zhang, Jiaqi ; Zhang, Lichao ; Tu, Ye ; Xin, Meng

BACKGROUND AND PURPOSEActivation of AMP-activated protein kinase (AMPK) is essential in maintaining the epithelial tight junction (TJ) barrier. Berberine, a phytochemical AMPK agonist, has been widely reported to ameliorate colitis. Berberine or AMPK activation inhibits cytoskeletal contraction induced by myosin light chain kinase (MLCK), thereby ameliorating TJ barrier defects. We previously found that swiprosin-1, an actin-binding protein, affects MLCK expression. Here, we aimed to reveal the role of swiprosin-1 in the regulation of AMPK/MLCK by berberine.METHODSCaco-2 monolayer transfected with AMPKα1 (or swiprosin-1) siRNA was treated with berberine after being stimulated with TNFα/IFNγ to assess the effect on the TJ barrier. Intestinal epithelial conditional knockout mice for AMPKα1 (or swiprosin-1) were treated with berberine after experimental colitis to evaluate the effect on the TJ barrier. TJ integrity was evaluated by immunoblotting and immunofluorescence for ZO-1 and Occludin.RESULTSThe protection of berberine against TJ barrier damage was blocked by AMPK inhibitor or knockout of AMPKα1 in epithelial cells. Swiprosin-1 was distributed in colonic epithelial cells and upregulated in colitis. Knockout of swiprosin-1 in intestinal epithelial cells ameliorated TJ barrier damage and abolished the protective effect of berberine. Impaired assembly of TJ caused by overexpression of swiprosin-1 was alleviated by MLCK inhibitor, and inhibition of the MLCK pathway by berberine also required the presence of swiprosin-1. In addition, berberine downregulated swiprosin-1 expression in an AMPK-dependent manner.CONCLUSIONSwiprosin-1 may be a key intermediate molecule in the regulation of the AMPK/MLCK pathway by berberine to attenuate colitis-induced TJ barrier damage.

01 Dec 2024·International Immunopharmacology

Isodeoxyelephantopin ameliorates LPS-induced acute peritonitis by inhibiting NLRP3 inflammasome in vitro and in vivo

Article

Author: Chen, Lifeng ; Liu, Zhong ; Shen, Zehui ; Zhang, Dongli ; Zhang, Zhimeng ; Zhang, Chen ; Qiu, Honghong ; Li, Junhao ; Guo, Xindong ; Li, Hengzhen ; An, Ran

Isodeoxyelephantopin (IDET), a sesquiterpene lactone compound isolated from the Asteraceae plant Inula helenium, has been demonstrated to possess excellent antimicrobial, antidiabetic, hepatoprotective, wound healing, anti-inflammatory, and anticancer activities. However, the underlying mechanisms of IDET's anti-inflammatory properties remain unclear. In this study, we investigated the anti-inflammatory effects and mechanisms of IDET using both in vitro and in vivo models. Our findings revealed that IDET dose-dependently inhibited the upregulation of inflammatory cytokines (IL-1β, IL-6, TNF-α) and pro-inflammatory chemokines (MCP-1, CCL20) induced by Lipopolysaccharide (LPS). IDET suppressed the activation of cyclooxygenase-2 (COX-2) and the NLRP3 inflammasome. Subsequent mechanistic investigations demonstrated that IDET inhibited the mRNA and protein levels of Txnip, FOXO1, and EFhd2 in THP-1 cells in a time- and concentration-dependent manner. Furthermore, in an LPS-induced acute peritonitis mouse model, IDET effectively ameliorated symptoms, preserved ileal tissue integrity, attenuated immune cell infiltration, and reduced the expression of inflammatory cytokines in mouse serum. Notably, IDET exhibited an improvement in acute peritonitis by inhibiting the activation of NLRP3 inflammasome. Overall, our study highlights the significant anti-inflammatory activity of IDET, providing valuable insights into its therapeutic potential for acute peritonitis.

01 Sep 2024·Journal of Hepatology

Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis

Article

Author: Fu, Jiang-Tao ; Lu, Guo-Dong ; Liu, Xingguang ; Liu, Yi ; Wang, Hua ; Cao, Qi ; Tong, Jie ; Wu, Wen-Bin ; Li, Xiang ; Meng, Hong-Bo ; Liang, Hai-Yan ; Zhuang, Chunlin ; Liu, Jian ; Zhang, Jia-Bao ; Shen, Fu-Ming ; Li, Dong-Jie ; Wang, Xu-Jie ; Wang, Zhi-Bin ; Wang, Pei ; Chen, Yi-Ting ; Zhang, Yuefan ; Zhu, Jia-Hui ; Sheng, Chunquan ; Yu, Yongsheng

BACKGROUND & AIMSThe precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH.METHODSHepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target.RESULTSEFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4⁺ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4⁺/CD8⁺ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice.CONCLUSIONOur study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment.IMPACT AND IMPLICATIONSNon-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

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EFHD2

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